This is an application for renewal of the Research Scientist Award by Mary Jeanne Kreek, MD. Narcotic addiction continues to be a major problem in the United States, with heroin abuse at some time identified in around 2 million persons, and regular use of heroin in over one-half million persons. The second largest risk group for the development of AIDS and for presence of infection with the human immunodeficiency virus (HIV) are parenteral drug abusers, primarily heroin addicts. This group may be the primary source of spread of HIV to the heterosexual population and to infants. At this time approximately 75,000 former heroin addicts are in chronic methadone maintenance treatment; however waiting lists for treatment continue to grow. Cocaine abuse including abuse by smoking the new free-base "crack" form, the most rapidly increasing drug abuse problem, with around 6 million people in the U.S. using cocaine regularly. Although several studies on treatment of cocaine abuse are in progress, to date there is no effective treatment generally available. Knowledge as to the biological basis of narcotic addition, although increasing, remains incomplete; even less is known about the biological basis of cocaine dependency in humans. The overall objectives of our proposed studies, which will involve both clinical and experimental research, as well as new technique development, will continue to focus on: 1) studies of disposition, metabolism, and drug interactions of addictive drugs and drugs used in the management of addictions; 2) studies of the physiological and pharmacological effects of opioids, opioid antagonists, and cocaine on neuroendocrine, gastroenterological, hepatic and immunological function, with emphasis on elucidating the biological correlates of treatment of addictions, the roles of endogenous opioids in normal physiology and in pathological states, and the possible relationships of defined physiological effects of the metabolic basis of addictive disease; and 3) surveillance of patients in chronic pharmacological treatment of narcotic addiction, and also cocaine dependency, coupled with studies of the natural history, during treatment, of co-existing major medical problems, especially alcoholic liver disease, hepatitis-B, hepatitis delta, and HIV infections, all of which are major public health problems.